Effects of PS-341 on the Activity and Composition of Proteasomes in Multiple Myeloma Cells

Altun, Mikael; Galardy, Paul J.; Shringarpure, Reshma; Hideshima, Teru; LeBlanc, Richard; Anderson, Kenneth C.; Ploegh, Hidde L.; Kessler, Benedikt M.

doi:10.1158/0008-5472.can-05-0506

Cited by 132 publications

(114 citation statements)

References 29 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…Slightly higher concentrations of Bortezomib were required to achieve inhibition of b-5i, b-2i, and b-1i. A recent study also showed that Bortezomib inhibits the immunoproteasome in MM cells (Altun et al, 2005). It is likely that blockade of one or more of these proteasomal activities along with the kinetics of inhibition confer therapeutic advantage.…”

mentioning

confidence: 98%

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

2006

View full text Add to dashboard Cite

Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/ refractory MM patients. The systemic regulation of protein synthesis and protein degradation is essential for normal cellular functioning. The ubiquitinproteasome pathway mediates intracellular protein degradation: first, protein is marked with a chain of small polypeptides called ubiquitin; E1 ubiquitin enzyme then activates ubiquitin and links it to the ubiquitin-conjugating enzyme E2 in an ATP-dependent manner; E3 ubiquitin ligase then links the ubiquitin molecule to the protein; a long polypeptide chain of ubiquitin moieties is formed; and finally, a multi-enzyme proteolytic complex 26S proteasome degrades protein into small fragments in an ATPdependent manner.

show abstract

mentioning

confidence: 98%

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

2006

View full text Add to dashboard Cite

show abstract

“…It has been shown that 3 HLA-A*0201 restricted epitopes (E7 [11][12][13][14][15][16][17][18][19][20] , E7 82-90 and E7 [86][87][88][89][90][91][92][93] ) induce CTL responses in HLA-A*0201 transgenic mice, and the generated CTLs lyse HLA-A*0201 1 HPV-16-positive CaSki cells. 34 As reported by Muderspach et al, 35 increase of E7 epitope-specific reactivity in cytokine release and cytotoxicity assays was demonstrated in 10 of 16 HPV-16-positive HLA-A*0201 1 patients with high-grade cervical or vulvar CIN after vaccination with either E7 [11][12][13][14][15][16][17][18][19][20] or E7 86-93 epitopes, and a proportion of these patients achieved partial clearance of virus infections and regression of lesions. Therefore, we sought to identify HLA-A*2402-restricted CTL epitopes from HPV-16 E6 and E7 oncoproteins by reverse immunology to facilitate immunotherapy for cervical cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…14 Bortezomib is a selective but reversible inhibitor of both standard proteasomes and immunoproteasomes. [15][16][17][18] In the present study, using a reverse immunological approach, we identified an HLA-A*2402-restricted HPV-16 E6-derived nonameric epitope, E6 [49][50][51][52][53][54][55][56][57] . A CD8 1 T cell clone, specific for this epitope, initially failed to recognize untreated HPV-16 1 cervical cancer cell lines; however, recognition was evident on bortezomib treatment, particularly with simultaneous IFN-g treatment in combination.…”

mentioning

confidence: 99%

Identification of an HLA‐A24‐restricted cytotoxic T lymphocyte epitope from human papillomavirus type‐16 E6: The combined effects of bortezomib and interferon‐γ on the presentation of a cryptic epitope

Akatsuka

Nawa

Kondo

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

About 50% of cervical cancers are associated with human papillomavirus type 16 (HPV-16), and since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in the tumor cells, they are attractive targets for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. Nevertheless, only a limited number of HPV-16 E6 epitopes have been identified to date. Using reverse immunological methods, we have generated a CTL clone against the HPV-16 E6 49-57 epitope restricted by HLA-A*2402, which is the most common allele in Japan and relatively frequent worldwide, capable of lysing 293T cells transduced with HLA-A*2402 and HPV-16 E6. Although it was unable to recognize the SiHa cervical cancer cell line positive for HPV-16 and HLA-A*2402, the cells became susceptible to lysis when transduced with E6-E7 genes, which was unexpectedly offset by pretreatment with interferon (IFN)-c alone. Interestingly, however, combined pretreatment with a proteasome inhibitor, bortezomib and IFN-c fully restored CTL-mediated lysis of the original SiHa cells. Furthermore, such intervention of 2 of 4 other cervical cancer cell lines expressing HPV-16 E6 and HLA-A*2402 was found to induce IFN-c production by specific CTLs. Tetramer analysis further revealed that induction of E6 49-57 -specific T cells was possible in 5 of 7 patients with HPV-16-positive high grade cervical intraepithelial neoplasia or cervical cancer by in vitro stimulation with E6 49-57 peptide. Thus, these findings together indicate that E6 49-57 is a candidate epitope for immunotherapy and immunological monitoring of such patients. ' 2006 Wiley-Liss, Inc.Key words: cytotoxic T lymphocyte; tumor immunity; epitope, cervical neoplasm; bortezomib Cervical cancer, the second most common cancer in women worldwide, with 250,000 new cases diagnosed each year, 1 is causally linked with human papillomavirus (HPV), the first proposed necessary cause of a human cancer as assessed by the World Health Organization. 2 High-risk HPV-16 is the most common type in all countries, with an overall prevalence of more than 50% in cervical cancers, 3 and 42.4% in Japanese patients. 4 Approximately 95% of HPV infections of the anogenital tract resolve spontaneously because of immune responses, 5 and the risk of cervical cancer is markedly increased in patients with immunodeficiency. [6][7][8] These findings suggest that the immune system plays a pivotal role in preventing development and progression of cervical cancer.Two HPV oncoproteins, E6 and E7, which can inhibit the tumor suppressors, p53 and RB respectively, are constitutively expressed in cervical cancer cells and appear to be required to maintain their malignant growth. 9 These viral oncoproteins, which are not present in normal cells, have been considered to be attractive targets for specific immunotherapy against cervical cancer, and identification and characterization of cytotoxic T lymphocyte (CTL) epitopes for HPV have facilitated the development of peptide vaccines against cervical cancer. Most of the CTL epitopes identified to date ...

show abstract

“…Proteasome-directed ABPs have been used to evaluate the specificity of bortezomib, a clinically approved proteasome inhibitor for the treatment of multiple myeloma [37,38]. Myeloma cells were cultured in the presence or absence of bortezomib, incubated with a cell-permeable, proteasome-specific ABP, lysed, and then analyzed by gel electrophoresis.…”

Section: Enzyme Inhibitor Discovery and Verificationmentioning

confidence: 99%

“…Myeloma cells were cultured in the presence or absence of bortezomib, incubated with a cell-permeable, proteasome-specific ABP, lysed, and then analyzed by gel electrophoresis. Results from these experiments revealed that only the activities of the β1/β1i and β5/β5i subunits of the proteasome were inhibited by bortezomib [37,38]. The cancer drug, paclitaxel, used to treat breast and ovarian cancers, has also been tested for its efficacy in a cell-based assay using a wortmannin-containing ABP that targets polo-like kinase 1 (PLK1), an enzyme with highly elevated activity in the M phase of the cell cycle [39].…”

Section: Enzyme Inhibitor Discovery and Verificationmentioning

confidence: 99%

Application of activity-based probes to the study of enzymes involved in cancer progression

Paulick

Bogyo

2008

Current Opinion in Genetics & Development

View full text Add to dashboard Cite

SummaryMany tumor cells have elevated levels of hydrolytic and proteolytic enzymes, presumably to aid in key processes such as angiogenesis, cancer cell invasion, and metastasis. Since the activities of these enzymes are often regulated by post-translational mechanisms, their functional roles in cancer progression are difficult to study using traditional genomic and proteomic methods. Thus, methods that allow for the direct monitoring of enzyme activity in a physiologically relevant environment are required to better understand the roles of specific players in the complex process of tumorigenesis. This review highlights advances in the field of activity-based proteomics, which uses small molecules known as activity-based probes (ABPs) that covalently bind to the catalytic site of target enzymes. We discuss the application of ABPs to cancer biology, specifically to the discovery of tumor biomarkers, the screening of enzyme inhibitors, and the imaging of enzymes implicated in cancer.

show abstract

Effects of PS-341 on the Activity and Composition of Proteasomes in Multiple Myeloma Cells

Cited by 132 publications

References 29 publications

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

A novel proteasome inhibitor NPI-0052 as an anticancer therapy

Identification of an HLA‐A24‐restricted cytotoxic T lymphocyte epitope from human papillomavirus type‐16 E6: The combined effects of bortezomib and interferon‐γ on the presentation of a cryptic epitope

Application of activity-based probes to the study of enzymes involved in cancer progression

Contact Info

Product

Resources

About